Unknown

Dataset Information

0

B cell-intrinsic CD84 and Ly108 maintain germinal center B cell tolerance.


ABSTRACT: Signaling lymphocyte activation molecules (SLAMs) play an integral role in immune regulation. Polymorphisms in the SLAM family receptors are implicated in human and mouse model of lupus disease. The lupus-associated, somatically mutated, and class-switched pathogenic autoantibodies are generated in spontaneously developed germinal centers (GCs) in secondary lymphoid organs. The role and mechanism of B cell-intrinsic expression of polymorphic SLAM receptors that affect B cell tolerance at the GC checkpoint are not clear. In this study, we generated several bacterial artificial chromosome-transgenic mice that overexpress C57BL/6 (B6) alleles of different SLAM family genes on an autoimmune-prone B6.Sle1b background. B6.Sle1b mice overexpressing B6-derived Ly108 and CD84 exhibit a significant reduction in the spontaneously developed GC response and autoantibody production compared with B6.Sle1b mice. These data suggest a prominent role for Sle1b-derived Ly108 and CD84 in altering the GC checkpoint. We further confirm that expression of lupus-associated CD84 and Ly108 specifically on GC B cells in B6.Sle1b mice is sufficient to break B cell tolerance, leading to an increase in autoantibody production. In addition, we observe that B6.Sle1b B cells have reduced BCR signaling and a lower frequency of B cell-T cell conjugates; the reverse is seen in B6.Sle1b mice overexpressing B6 alleles of CD84 and Ly108. Finally, we find a significant decrease in apoptotic GC B cells in B6.Sle1b mice compared with B6 controls. Our study establishes a central role for GC B cell-specific CD84 and Ly108 expression in maintaining B cell tolerance in GCs and in preventing autoimmunity.

SUBMITTER: Wong EB 

PROVIDER: S-EPMC4402266 | BioStudies | 2015-01-01

REPOSITORIES: biostudies

Similar Datasets

2012-01-01 | S-EPMC3518623 | BioStudies
2016-01-01 | S-EPMC4880187 | BioStudies
2011-01-01 | S-EPMC3135348 | BioStudies
2014-01-01 | S-EPMC4201954 | BioStudies
2011-01-01 | S-EPMC3110600 | BioStudies
2020-01-01 | S-EPMC7683613 | BioStudies
1000-01-01 | S-EPMC4564365 | BioStudies
2012-01-01 | S-EPMC3311760 | BioStudies
2010-01-01 | S-EPMC2830297 | BioStudies
2014-01-01 | S-EPMC4002579 | BioStudies